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SOLID-STATE PROPERTIES OFPHARMACEUTICAL MATERIALS
SOLID-STATE PROPERTIES OFPHARMACEUTICAL MATERIALS
STEPHEN R. BYRNGEORGE ZOGRAFIXIAOMING (SEAN) CHEN
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Library of Congress Cataloging-in-Publication Data:Names: Byrn, Stephen R., author. | Zografi, George, author. | Chen, Xiaoming (Sean), author.Title: Solid-state properties of pharmaceutical materials / Stephen R. Byrn, George Zografi,
Xiaoming (Sean) Chen.Description: Hoboken, NJ : John Wiley & Sons, 2017. | Includes index.Identifiers: LCCN 2017005555 (print) | LCCN 2017008527 (ebook) | ISBN 9781118145302 (cloth) |
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CONTENTS
Preface xi
Acknowledgments xiii
1 Solid-State Properties and Pharmaceutical Development 1
1.1 Introduction, 11.2 Solid-State Forms, 11.3 ICH Q6A Decision Trees, 61.4 “Big Questions” for Drug Development, 61.5 Accelerating Drug Development, 91.6 Solid-State Chemistry in Preformulation and Formulation, 111.7 Learning Before Doing and Quality by Design, 141.8 Performance and Stability in Pharmaceutical Development, 171.9 Moisture Uptake, 181.10 Solid-State Reactions, 191.11 Noninteracting Formulations: Physical Characterizations, 19References, 20
2 Polymorphs 22
2.1 Introduction, 222.2 How are Polymorphs Formed?, 222.3 Structural Aspect of Polymorphs, 232.4 Physical, Chemical, and Mechanical Properties, 242.5 Thermodynamic Stability of Polymorphs, 272.6 Polymorph Conversion, 322.7 Control of Polymorphs, 342.8 Polymorph Screening, 352.9 Polymorph Prediction, 36References, 36
3 Solvates and Hydrates 38
3.1 Introduction, 383.2 Pharmaceutical Importance of Hydrates, 38
v
vi CONTENTS
3.3 Classification of Pharmaceutical Hydrates, 403.4 Water Activity, 423.5 Stoichiometric Hydrates, 433.6 Nonstoichiometric Hydrates, 443.7 Hydration/Dehydration, 453.8 Preparation and Characterization of Hydrates and Solvates, 45References, 46
4 Pharmaceutical Salts 48
4.1 Introduction, 484.2 Importance of Pharmaceutical Salts, 484.3 Weak Acid, Weak Base, and Salt, 494.4 pH-Solubility Profiles of Ionizable Compounds, 514.5 Solubility, Dissolution, and Bioavailability of Pharmaceutical Salts, 534.6 Physical Stability of Pharmaceutical Salts, 564.7 Strategies for Salt Selection, 57References, 59
5 Pharmaceutical Cocrystals 60
5.1 Introduction, 605.2 Cocrystals and Crystal Engineering, 605.3 Solubility Phase Diagrams for Cocrystals, 625.4 Preparation of Cocrystals, 635.5 Dissolution and Bioavailability of Cocrystals, 645.6 Comparison of Pharmaceutical Salts and Cocrystals, 66References, 68
6 Amorphous Solids 69
6.1 Introduction, 696.2 The Formation of Amorphous Solids, 706.3 Methods of Preparing Amorphous Solids, 716.4 The Glass Transition Temperature, 726.5 Structural Features of Amorphous Solids, 756.6 Molecular Mobility, 776.7 Mixtures of Amorphous Solids, 84References, 87
7 Crystal Mesophases and Nanocrystals 89
7.1 Introduction, 897.2 Overview of Crystal Mesophases, 897.3 Liquid Crystals, 907.4 Conformationally Disordered (Condis) Crystals, 957.5 Plastic Crystals, 957.6 Nanocrystals, 96References, 97
8 X-Ray Crystallography and Crystal Packing Analysis 99
8.1 Introduction, 998.2 Crystals, 998.3 Miller Indices and Crystal Faces, 998.4 Determination of the Miller Indices of the Faces of a Crystal, 101
CONTENTS vii
8.5 Determination of Crystal Structure, 103References, 106
9 X-Ray Powder Diffraction 107
9.1 Introduction, 1079.2 X-Ray Powder Diffraction of Crystalline Materials, 1079.3 Qualitative Analysis of Crystalline Materials, 1099.4 Phase Transformations, 1109.5 Quantitative Phase Analysis Using XRPD, 1119.6 Solving Crystal Structures Using Powder X-Ray Diffraction, 1149.7 X-Ray Diffraction of Amorphous and Crystal Mesophase Forms, 1169.8 Pair Distribution Function, 1179.9 X-Ray Diffractometers, 1199.10 Variable Temperature XRPD, 121References, 122
10 Differential Scanning Calorimetry and Thermogravimetric Analysis 124
10.1 Introduction, 12410.2 The Basics of Differential Scanning Calorimetry, 12410.3 Thermal Transitions of Pharmaceutical Materials, 12510.4 DSC Instrumentation, 12810.5 Thermogravimetric Analysis, 13210.6 Operating a TGA Instrument, 13310.7 Evolved Gas Analysis, 13310.8 Applications of DSC and TGA, 13410.9 Summary of Using DSC and TGA, 139References, 140
11 Microscopy 142
11.1 Introduction, 14211.2 Light Microscopy, 14211.3 Polarized Light Microscopy, 14411.4 Thermal Microscopy, 14411.5 Functionality of the Light Microscope, 14511.6 Digital Microscope, 14611.7 Application of Light Microscopy to Pharmaceutical Materials, 14611.8 Scanning Electron Microscope, 15311.9 Environmental Scanning Electron Microscopy, 15511.10 Atomic Force Microscopy, 155References, 157
12 Vibrational Spectroscopy 159
12.1 Introduction, 15912.2 The Nature of Molecular Vibrations, 16012.3 Fourier Transformed Infrared Spectroscopy, 16112.4 Material Characterization by FT-IR Spectroscopy, 16212.5 FT-IR Instrumentation, 16412.6 Diffuse Reflectance FT-IR, 16512.7 Attenuated Total Reflectance FT-IR, 16612.8 FT-IR Microscopy, 16712.9 Near Infrared Spectroscopy, 168
viii CONTENTS
12.10 Raman Spectroscopy, 17012.11 Raman Instrumentation and Sampling, 17112.12 Raman Microscope, 17312.13 Terahertz Spectroscopy, 17512.14 Comparison of FT-IR, NIR, Raman, and Terahertz Spectroscopy, 176References, 178
13 Solid-State NMR Spectroscopy 180
13.1 Introduction, 18013.2 An Overview of Solid-State 13C CP/MAS NMR Spectroscopy, 18013.3 Solid-State NMR Studies of Pharmaceuticals, 18513.4 Phase Identification in Dosage Forms, 18613.5 Other Basic Solid-State NMR Experiments Useful for Pharmaceutical Analysis, 18913.6 Determination of the Domain Structure of Amorphous Dispersions Using
Solid-State NMR, 192References, 196
14 Particle and Powder Analysis 197
14.1 Introduction, 19714.2 Particles in Pharmaceutical Systems, 19714.3 Particle Size and Shape, 19914.4 Particle Size Distribution, 20014.5 Dynamic Light Scattering, 20214.6 Zeta Potential, 20314.7 Laser Diffraction, 20514.8 Dynamic Image Analysis, 20614.9 Sieve Analysis, 20814.10 Bulk Properties of Pharmaceutical Particulates and Powders, 20814.11 Surface Area Measurement, 209References, 211
15 Hygroscopic Properties of Solids 213
15.1 Introduction, 21315.2 Water Vapor Sorption–Desorption, 21415.3 Water Vapor Sorption Isotherms, Relative Humidity, and Water Activity, 21415.4 Measurement of Water Content and Water Vapor Sorption/Desorption Isotherms, 21615.5 Modes of Water Vapor Sorption, 218References, 229
16 Mechanical Properties of Pharmaceutical Materials 231
16.1 Introduction, 23116.2 Stress and Strain, 23116.3 Elasticity, 23216.4 Plasticity, 23316.5 Viscoelasticity, 23416.6 Brittleness, 23516.7 Hardness, 23616.8 Powder Compression, 23716.9 Powder Compression Models and Compressibility, 23816.10 Compactibility and Tensile Strength, 23916.11 Effect of Solid Form on Mechanical Properties, 23916.12 Effect of Moisture on Mechanical Properties, 24216.13 Methods for Testing Mechanical Properties: Beam Bending, 243
CONTENTS ix
16.14 Nanoindentation, 246References, 247
17 Solubility and Dissolution 249
17.1 Introduction, 24917.2 Principle Concepts Associated with Solubility, 24917.3 Prediction of Aqueous Drug Solubility, 25017.4 Solubility of Pharmaceutical Solid Forms, 25217.5 Solubility Determination Using the Shake Flask Method, 25317.6 High Throughput Screening of Solubility, 25417.7 Solubility Measurement of Metastable Forms, 25517.8 Kinetic Solubility Measurement, 25617.9 Solubility Determination of Drugs in Polymer Matrices, 25617.10 Dissolution Testing, 25717.11 Nonsink Dissolution Test, 26017.12 Intrinsic Dissolution Studies, 262References, 263
18 Physical Stability of Solids 265
18.1 Introduction, 26518.2 Underlying Basis for Physical Instability in Pharmaceutical Systems, 26618.3 Disorder in Crystals, 26718.4 Examples of the Role of Process-Induced Disorder in Solid-State Physical Instability
in Pharmaceutical Systems, 27418.5 Considerations in Evaluating Solid-State Physical Stability, 276References, 277
19 Chemical Stability of Solids 279
19.1 Introduction, 27919.2 Examples of Chemical Reactivity in the Solid State, 27919.3 Some General Principles that Establish the Rate of Chemical Reactions in Solution, 28219.4 The Role of Crystal Defects in Solid-State Reactions, 28619.5 Chemical Reactivity in the Amorphous Solid State, 29019.6 Chemical Reactivity and Processed-Induced Disorder, 29219.7 The Effects of Residual Water on Solid-State Chemical Reactivity, 29419.8 Drug–Excipient Interactions, 29819.9 Summary, 300References, 300
20 Solid-State Properties of Proteins 302
20.1 Introduction, 30220.2 Solution Properties of Proteins, 30220.3 Amorphous Properties of Proteins, 30620.4 Crystalline Properties of Proteins, 30720.5 Local Molecular Motions and the Dynamical Transitional Temperature, Td, 30820.6 Solid-State Physical and Chemical Stability of Proteins, 31020.7 Cryoprotection and Lyoprotection, 311References, 311
21 Form Selection of Active Pharmaceutical Ingredients 313
21.1 Introduction, 31321.2 Form Selection, 313
x CONTENTS
21.3 Amorphous form Screening, 31521.4 Salt Selection, 31621.5 Cocrystal Screening, 31821.6 Polymorph Screening, 32021.7 Slurrying, 32121.8 High Throughput Screening, 32221.9 Crystallization in Confined Space, 32321.10 Nonsolvent-Based Polymorph Screening, 32521.11 Polymer-Induced Heteronucleation, 32521.12 Physical Characterization, 32621.13 Thermodynamic Stability and form Selection, 327References, 328
22 Mixture Analysis 331
22.1 Introduction, 33122.2 Limitations of Wet Chemistry, 33122.3 Pharmaceutical Analysis in the Solid State, 33222.4 Measurement of Amorphous Content, 33522.5 Detection of the Degree of Crystallinity, 33722.6 Quantification of Mixtures of Polymorphs, 33922.7 Salt and Free form Composition, 34022.8 Process Analytical Technology, 342References, 348
23 Product Development 351
23.1 Chemistry, Manufacture, and Control, 35123.2 Preformulation, 35323.3 Drug Excipient Compatibility, 35423.4 Solid Dispersions, 35523.5 Abuse-Deterrent Dosage Forms, 36123.6 Drug-Eluting Stents, 36323.7 Dry Powder Inhalers (DPI), 36523.8 Lyophilization and Biopharmaceutical Products, 368References, 372
24 Quality by Design 375
24.1 Introduction, 37524.2 Quality by Design Wheel, 37524.3 Learning Before Doing, 37924.4 Risk-Based Orientation, 38024.5 API Attributes and Process Design, 38124.6 Development and Design Space, 38124.7 Process Design: Crystallization, 38524.8 Phase Transformations During Wet Granulation, 38624.9 Dissolution Tests with an IVIVC for Quality by Design, 38724.10 Conclusion, 388References, 388
Index 389
PREFACE
The aim of this book is to illustrate the importance of under-standing the fundamental solid-state properties of pharma-ceutical materials during the development of solid pharma-ceutical products and to lay out general strategies for thephysical characterization of solids using various analyticaltools. Generally, great emphasis is understandably placed onthe discovery of new active pharmaceutical ingredients (API)for the cure, treatment, and prevention of various acute andchronic diseases. However, it has been firmly establishedthat the ability to obtain successful drug products in an effi-cient and timely manner strongly depends on the formulationand manufacture of stable and bioavailable drugs into usefulproducts, where various physical and chemical characteris-tics play an essential role. In essence, it can be said, therefore,that a “drug” is more than a molecule, rather being part of acomplex mixture of materials with physical chemical char-acteristics that can determine therapeutic success or failure.
The book is divided into four parts. The first part focuseson the various phases or forms that solids can assume, includ-ing polymorphs, solvates/hydrates, salts, cocrystals, amor-phous forms, crystal mesophases, and nanocrystals, and var-ious issues related to their relative stability and tendencies toundergo transformations. The second part focuses on the keymethods of solid-state analysis such as X-ray crystallogra-phy, X-ray powder diffraction, thermal analysis, microscopy,
vibrational spectroscopy, and solid-state NMR. The third partreviews critical physical attributes of pharmaceutical mate-rials, mainly related to drug substances, including particlesize/surface area, hygroscopicity, mechanical properties, sol-ubility, and physical and chemical stability. The fourth partof the book builds on the first three parts to illustrate howan understanding of the various properties of pharmaceuticalmaterials may be used for (1) the rational selection of drugsolid form, (2) the analysis of mixtures of various solid formswithin the drug substance and the drug product, (3) establish-ing rational protocols and strategies for carrying out efficientand successful product development, and (4) applicationsof appropriate manufacturing and control procedures, usingQuality by Design, and other strategies that lead to safe andeffective products with a minimum of resources and time.
Furthermore, we have attempted to design this book insuch a way that it can be used by preformulation and for-mulation scientists, process engineers, analytical chemists,quality assurance and quality control managers, regulators,and other researchers, who all contribute to the drug devel-opment process. We hope that by presenting a mixture offundamental solid-state science and its practical applicationsto the drug development process we will have helped allinvolved to gain a greater perspective of the importance ofboth aspects.
xi
ACKNOWLEDGMENTS
Stephen Byrn credits his wife, Sally, and his family, withoutwhom this would not have been possible.
George Zografi would like to thank his wife, Dorothy,and his family for their continuous support throughout hisprofessional career.
Xiaoming (Sean) Chen is very grateful for the love andsupport from his wife, Feifei Tian, and his sons, in the prepa-ration of this book.
We extend our deep appreciation to Bob Esposito,Kshitija Iyer, Purvi Patel, Michael Leventhal and MelissaYanuzzi at John Wiley & Sons, Inc., and Suresh Srinivasanat Aptara, who have been supportive and patient during thepreparation of this book.
xiii
1SOLID-STATE PROPERTIES AND PHARMACEUTICALDEVELOPMENT
1.1 INTRODUCTION
Solid-state chemistry and the solid-state properties of phar-maceutical materials play an ever increasing and importantrole in pharmaceutical development. There is much moreemphasis on physical characterization since the release ofthe International Committee on Harmonization (ICH) Q6Aguidance on specifications. This guidance directs the scientistto determine what solid form is present in the drug substance(active pharmaceutical ingredient [API]) and drug product. Itdirects themanufacturer to “knowwhat they have.” Addition-ally, the ICH Q8 guidance on development and the ICH Q9guidance on risk management require a firm understandingof how the medicine was developed and any risks involved.
There are many more poorly soluble drugs under devel-opment. In many cases, the solid form of the API andthe solid form and formulation in the drug product deter-mine apparent solubility that in turn determines blood lev-els. That is, the formulation determines bioavailability andtherapeutic response. In these cases, it is even more impor-tant to physically characterize the API form and the formu-lations. Furthermore, the vast majority of medicines (drugproducts) are solids and those drug products that are notsolids often start with solid APIs. In addition to solubil-ity and bioavailability, the solid form may affect stability,flow, compression, hygroscopicity, and a number of otherproperties.
This book focuses on solid-state properties of pharmaceu-tical materials and methods of determining these properties.The authors have made every effort to include examples and
case studies in order to illustrate the importance of knowingwhat you have. This book will focus on solid-state prop-erties and general strategies for physical characterization.Case studies and practical examples will be emphasized. Inmany respects, this book will illustrate that a medicine ismore than a molecule. Additional goals include providing afull physical/analytical/operational definition of the differentsolid forms as well as other terms frequently used in phar-maceutical materials science including: polymorph, solvate,amorphous form, habit, nucleation, transformation, dissolu-tion, solubility, and stability.
1.2 SOLID-STATE FORMS
Pharmaceutical materials can exist in a crystalline or amor-phous state. Figure 1.1 illustrates the crystalline state as aperfectly ordered solid with molecules (circles) packed in anorderly array. Figure 1.1 illustrates an amorphous materialas a disordered material with only short-range order. Crys-talline materials give an X-ray diffraction pattern becauseBragg planes exist in the material (see Figure 1.2). Amor-phous materials do not give a diffraction pattern (Figure 1.2).Of course, there are many interesting cases where a phar-maceutical material shows an intermediate degree of orderfalling somewhere between the highly ordered crystallinestate and the disordered amorphous state. From a thermody-namic point of view, crystalline materials are more stable butthe rate of transformation of amorphous materials to crys-talline materials can be highly variable [1].
Solid-State Properties of Pharmaceutical Materials, First Edition. Stephen R. Byrn, George Zografi and Xiaoming (Sean) Chen.© 2017 John Wiley & Sons, Inc. Published 2017 by John Wiley & Sons, Inc.
1
2 SOLID-STATE PROPERTIES AND PHARMACEUTICAL DEVELOPMENT
FIGURE 1.1 Idealized view of crystalline (left panel) and amorphous (right panel) material. Inthis two-dimensional figure, the molecules are viewed as circles.
Crystals of a pharmaceutical material from differentsources can vary greatly in their size and shape. Typical parti-cles in different samplesmay resemble, for example, needles,rods, plates, and prisms. Such differences in shape are col-lectively referred to as differences in morphology. This termmerely acknowledges the fact of different shapes. It does notdistinguish among themany possible reasons for the different
shapes. Naturally, when different compounds are involved,different crystal shapes would be expected as a matter ofcourse. When batches of the same substance display crystalswith different morphology, however, further work is neededto determine whether the different shapes are indicative ofpolymorphs, solvates, or just habits. Because these distinc-tions can have a profound impact on drug performance, their
FIGURE 1.2 X-ray diffraction pattern of three samples, crystalline, low crystallinity, andamorphous.
SOLID-STATE FORMS 3
careful definition is very important to our discourse. At thistime, only brief definitions are presented.
� Polymorphs: When two crystals have the same chemicalcomposition but different internal structure (molecularpacking), they are polymorphic modifications, or poly-morphs (think of the three forms of carbon: diamond,graphite, and fullerenes). Polymorphs can result fromdifferent molecular packing, different molecular confor-mation, different tautomeric structure, or combinationsof these.
� Solvates: These crystal forms, in addition to containingmolecules of the same given substance, also containmolecules of solvent regularly incorporated into a uniquestructure (think ofwet, setting plaster: CaSO4 +2H2O→CaSO4⋅2H2O).
� Habits: Crystals are said to have different habits whensamples have the same chemical composition and thesame crystal structure (i.e., the same polymorph and unitcell) but display different shapes (think of snowflakes).
Together, these solid-state physical modifications of a com-pound are referred to as crystalline forms. When differencesbetween early batches of a substance are found by micro-scopic examination, for example, a reference to “form” isparticularly useful in the absence of information that allowsthe more accurate description of a given variant batch (i.e.,polymorph, solvate, habit, or amorphous material). The termpseudopolymorphism is applied frequently to designate sol-vates. These solid-state modifications have different physicalproperties.
To put these important definitions into a practical con-text, we consider two cases (aspirin and flufenamic acid)in which a drug was crystallized from several different sol-vents and different-shaped crystals resulted in each exper-iment. Although sometimes dramatically different shapeswere obtained upon changing solvents for the various crys-tallizations, the final interpretations in the two cases are dif-ferent. For aspirin, X-ray powder diffraction showed that allcrystals regardless of shape had the same diffraction pattern.Thus, the different shaped crystals are termed crystal habits.For flufenamic acid, the different shaped crystals had differ-ent X-ray powder diffraction patterns. Subsequent analysisshowed that the crystals did not contain solvent. Thus thesedifferent crystals are polymorphs.
Further analysis of the crystals from this case providesthe single crystal structure. The single crystal structuregives the locations of the atoms relative to a hypothetical unitcell. The unit cell is the smallest building block of a crys-tal. Figure 1.3 shows the unit cell of Form I of flufenamicacid. This unit cell contains four flufenamic acid molecules.Figure 1.4 shows a space-filling model of the contents ofthe flufenamic acid Form I unit cell. This figure illustratesKitaigorodskii’s close-packing theory, which requires thatthe molecules pack to minimize free volume [2].
Amorphous materials will be discussed in Chapter 6. Inthis introductory chapter as mentioned briefly above, amor-phous materials have no long range order and are thermody-namically metastable. An amorphous solid is characterizedby a unique glass transition temperature Tg, the temperatureat which it changes from a glass to a supercooled liquid orrubbery state. When T rises above Tg, the rigid solid can
COOH0
0
a
CF3HN
c
FIGURE 1.3 Single crystal structure the Form I polymorph of flufenamic acid (structure shownon the right panel).
4 SOLID-STATE PROPERTIES AND PHARMACEUTICAL DEVELOPMENT
FIGURE 1.4 Space filling drawing of the unit cell of flufenamicacid Form I.
flow and the corresponding increase in molecular mobilitycan result in crystallization or increased chemical reactiv-ity of the solid. Several historic papers describe some addi-tional details of amorphous materials. Pikal and coworkers atEli Lilly showed that amorphous materials can have lowerchemical stability [3], and Fukuoka et al. showed amorphousmaterials had a tendency to crystallize [4]. Nevertheless, insome cases, amorphous forms have been historically usedas products. An excellent example is novobiocin [5], whichexists in a crystalline and an amorphous form. The crys-talline form is poorly absorbed and does not provide thera-peutic blood levels; in contrast, the amorphous form is readilyabsorbed and is therapeutically active. Further studies showthat the solubility rate of the amorphous form is 70 timesgreater than the crystalline form in 0.1 N HCl at 25◦C whenparticles anhydrous crystal > amorphous
3. lower solubility,
4. narrow and (usually) higher melting point range,
5. harder,
6. brittle – slip and cleavage,
7. directionally dependent properties – anisotropy,
8. less compressible,
9. better flow and handling characteristics, and
10. less hygroscopic.
From this list, it is clear that crystalline materials are gen-erally more desirable unless they are so insoluble that theycannot be used as medicines.
Not only do polymorphs show different X-ray powderdiffraction patterns but they also have different unit cells,and different properties including thermal properties [6]. Fig-ure 1.5 shows the different crystal packing of the Forms I andII of sulfathiazole.
Additionally, polymorphs are characterized asmonotropicor enantiotropic depending upon their thermal properties[9, 10].
� Monotropic polymorphs exist if the transition tem-perature between forms is greater than the melt.In monotropic polymorphs, one form is most stablethroughout the temperature range.
� Enantiotropic polymorphs exist if the transition tem-perature between forms occurs before melting. In thiscase, one form is more stable at one temperature. At a
FIGURE 1.5 Crystal packing and unit cells (grey) of Forms I (left panel) and II (right panel)of sulfathiazole. The grey and black molecules in Form I indicate two unrelated molecules in theasymmetric unit. Source: Kruger and Gafner, 1971 [7, 8]. Redrawn from data published.
SOLID-STATE FORMS 5
different temperature the other form is most stable. Forflufenamic acid, Form I is most stable above the tran-sition temperature of 42◦C and Form III is most stablebelow the transition temperature. Practically, this meansthat slurrying at room temperature will convert Form Ito Form III.
Crystalline solvates contain solvents regularly incorporatedinto the crystal lattice. When the solvent is water the solidform is called a hydrate. Solvates and hydrates do not havethe same composition as unsolvated materials. Solvates andhydrates are sometimes referred to as pseudopolymorphs orsolvatomorphs. Interestingly, it is possible for solvates andhydrates to be polymorphic. In such a case one has polymor-phic solvates. Kuhnert Brandstatter in her 1971 book showedphotomicrographs of 16 solvates of estradiol [11]. Figure 1.6shows the crystal structure of caffeine monohydrate. Thecrystal of caffeine is built up by stacking the layers shown inFigure 1.6 on top of each other. Thus the hydrate moleculesare in tunnels in this solid form.
It is important to note that the FDA (Food and DrugAdministration) has defined polymorphs as “different crys-talline forms of the same drug substance. This may includesolvation or hydration products (also known as pseudopoly-morphs) and amorphous forms. Per the current regulatoryscheme, different polymorphic forms are considered the sameactive ingredients.” Thus, for purposes of registration, sci-entists are directed to define polymorphs more broadly toinclude amorphous forms, solvates, and hydrates.
Cocrystals, that is, two component crystals, are anothersolid material of interest. Like solvates, the new crystalline
FIGURE 1.6 Projection of the crystal structure of caffeinehydrate on the ab plane. Source: Burger and Ramberger, 1979[9, 10]. Reproduced with the permission of Springer.
FIGURE 1.7 Crystal structure of a cocrystal (2-methoxy-4-nitrophenol-4-(dimethylamino) pyridine (2:1)). The unit cell param-eters are a = 6.880, b = 38.40, c = 8.454, and the space group isPna21. Source: Burger and Ramberger, 1979 [9, 10]. Reproducedwith the permission of Springer.
structure imparts different properties including solubility,stability, andmechanical properties to thematerial. Of specialinterest are cocrystals with altered solubility or stability. Fig-ure 1.7 shows the crystal structure of a cocrystal of phenol and2-methoxy-4-nitrophenol–4-(dimethylamino)pyridine (2:1)[12]. The FDAhas recently released a draft guidance definingcocrystals as “Solids that are crystalline materials composedof two or more molecules in the same crystal lattice.”
Pharmaceutical salts are substances formed by a reactionof an acid and a base. The FDA has suggested the follow-ing definition of salts as “Any of numerous compounds thatresult from replacement of part or all of the acid hydrogenof an acid by a metal or a radical acting like a metal: anionic or electrovalent crystalline compound. Per the currentregulatory scheme, different salt forms of the same activemoiety are considered different active ingredients.” Whena carboxylic acid reacts with an amine a salt is typicallyformed (Scheme 1.1). However, the degree of proton transfercan vary depending on the acidity and basicity of the reactinggroups. The FDA definition seems to encompass all of thesematerials.
RCOOH + H2N − R′ ⟶ RCOO−⋯H3N+ − R
SCHEME 1.1
6 SOLID-STATE PROPERTIES AND PHARMACEUTICAL DEVELOPMENT
FIGURE 1.8 Crystal packing of calcium tolfenamate trihydrate showing hydrogen bonding net-work. The directions of the unit cell axis are (a) vertical, (c) across, and (b) out of the plane of thepaper. Source: Atassi, 2007 [13]. Reproduced with the permission of Purdue University.
Figure 1.8 shows the crystal structure of calcium tolfe-namate trihydrate. It is clear that the unit cell is composedof regions containing mostly hydrocarbon functional groupsand regions containing polar functionalities. This type ofcrystal packing is typical for salts.
1.3 ICH Q6A DECISION TREES
In 1995, Byrn et al. fromPurdueUniversity and the FDApub-lished a paper using decision trees to describe a strategy toidentify the best solid form early in development. In this way,it is possible to ensure uniformity of solid form in clinicaltrials and resolve solid-state issues before critical stages ofdevelopment. The decision trees also suggested appropriateanalytical methods for control. Four decision trees were pre-sented: polymorphs, hydrates/solvates, desolvated solvates,and amorphous forms [14].
In the late 1990s, the ICH used a similar decision treeapproach to describe how specification for the solid formin drug substances (API) and drug product should be deter-mined. Several decision trees were presented in the ICHQ6A document including decision trees on particle size andpolymorphs. The ICH utilized the broadened definition ofpolymorphs that includes hydrates, solvates, and amorphous
forms. The ICH decision trees are divided into three ques-tions as shown in Figures 1.9–1.11.
These three decision trees outline a strategy that is widelyused during drug development. Most firms conduct an earlypolymorph screen to address question number 1. Once newforms have been identified, they are physically characterized(solubility, stability, melting point) and an effort is made tounderstand whether these differences in properties will affectdrug product safety, performance, or efficacy. If the differentsolid forms can affect safety, efficacy, or performance thenquestion 3 is addressed by determining whether drug producttesting can detect changes in ratios of these forms. Addition-ally, the ratios of forms are monitored during stability studiesto make sure changes that affect performance, safety, or effi-cacy do not occur. Using this strategy, it is possible to findthe best solid form for development rapidly.
1.4 “BIG QUESTIONS” FOR DRUGDEVELOPMENT
In addition to selecting the solid form, Table 1.1 lists othercritical issues/measurements required for drug development.
Another way to think about drug development is to thinkof this process in terms of answering a series of questionswe call the “Big Questions.” These must be answered to be
“BIG QUESTIONS” FOR DRUG DEVELOPMENT 7
FIGURE 1.9 ICH Q6A question 1 on polymorphs: Can different polymorphs be formed? Source:ICH Harmonized Tripartite Guideline, 1999. Reproduced with the permission of ICH.
FIGURE 1.10 ICH Q6A question 2 on polymorphs: Do the forms have different properties (sol-ubility, stability, melting point)? Source: ICH Harmonized Tripartite Guideline, 1999. Reproducedwith the permission of ICH.
8 SOLID-STATE PROPERTIES AND PHARMACEUTICAL DEVELOPMENT
FIGURE 1.11 ICH Q6A question 3 on polymorphs: Does products performance testing provideadequate control I polymorph ratio changes (e.g., dissolution)? Source: ICH Harmonized TripartiteGuideline, 1999. Reproduced with the permission of ICH.
TABLE 1.1 Critical Issues for Drug Development
Polymorph selectionChemical synthesisSalt selection (optional)Assay/ImpuritiesParticle sizePhysical characterization and propertiesDissolution/solubilityConsistencyStabilityValidated methods/processesRegulatory issuesIntellectual property
able to develop a drug to clinical trials and beyond. Thesequestions are as follows:
� What is the structure of the compound?� What is the likely dose?� What is the route of administration and desired dosageform?
� What is the indication?� How difficult is it to synthesize?� How soluble is the compound/formulation?� How well is the compound absorbed? What is its BCS(Biopharmaceutical Classification System) class?
� What is the toxicology of the compound? What is itsNOAEL (no-observed-adverse-effect-level)?What is itsMTD (maximum tolerated dose)?
ACCELERATING DRUG DEVELOPMENT 9
� What biomarkers are available to monitor clinical trials?� What doses should be used for Phase 2 clinical trial?� What are its solid-state properties and physical charac-terization?
� How chemically stable is the compound?� How physically stable is the compound?� How well will the powder flow?� Is moisture an issue?� What is the design, composition, and manufacturingprocedure of the formulation/product?
As has already been discussed, the solubility of the compoundis a critical quality attribute important for specifications anddevelopment. The solubility of a solid substance is the con-centration at which the solution phase is in equilibrium witha given solid phase at a stated temperature and pressure.Under these conditions, the solid is neither dissolving norcontinuing to crystallize. Note that the definition implies thepresence of a specific solid phase. Once determined under thestated conditions, however, we can talk about the “solubility”of a given phase (e.g., a specific polymorph or pseudopoly-morph) as a quantity, even in the absence of that solid phase.Use of the term “equilibrium” in connection with crystalliz-ing systems requires clarification. When a substance exists inmore than one crystal form, that is, when other polymorphsare possible, only the least soluble of these at a given tem-perature is considered the most physically stable form at thattemperature, all others are considered to bemetastable forms.In given cases, a solution of a substance may be in apparentequilibrium with one of these metastable phases for a longtime, in which case, the system is in metastable equilibriumand is expressing the thermodynamic solubility of that solidform.
It is important to stress the difference between poly-morphs and solvates (pseudopolymorphs) at this point. Ifa solvate/pseudopolymorph exists, it is always (with fewexceptions) the most stable form in the solvent that producesthe pseudopolymorph.
Undersaturation pertains to solutions at a lower concentra-tion than the saturation value (i.e., diluted solutions). Crystalswill dissolve in undersaturated solutions. Saturation is thestate of a system where the solid is in equilibrium with thesolution, or in other words, the solution will neither dissolvecrystals nor let them grow (i.e., the concentration of the solu-tion represents the solubility value for that crystalline phase).Supersaturation pertains to solutions that, for one reason oranother (e.g., rapid cooling of a saturated solution withoutforming crystals), are at a higher concentration than the satu-ration value. Supersaturation is required for crystals to grow.
The solubility and permeability are combined to deter-mine the BCS class (Table 1.2). BCS class I drugs dis-solve easily and are easily transported into the blood stream
TABLE 1.2 Biopharmaceutical Classification System (BCS)
BCS Classification Solubility Permeability
BCS class I High HighBCS class II Low HighBCS class III High LowBCS class IV Low Low
because they are highly permeable with respect to the mem-branes in the gastrointestinal (GI) tract. BCS class III andIV drug have poor permeability and are generally difficultto develop. BCS class II drugs are of the greatest interest topharmaceutical scientists because the structure of the solid,the formulation, its physical character, and many other fac-tors are likely to have a significant effect on bioavailabil-ity and ultimately safety, performance, and efficacy. Severalimportant drugs that are widely prescribed are BCS ClassII including atorvastatin calcium, celecoxib, efavirenz, irbe-sartan, lopinavir, medroxyprogesterone acetate, raloxifenehydrochloride, simvastatin, andwarfarin sodium. Of themar-keted drugs nearly 70% are in BCS Class I or II with 31%being in BCS Class II. It has been estimated that as high as80% of the drugs under development are BCS Class II.
1.5 ACCELERATING DRUG DEVELOPMENT
Accelerating drug development has been a goal of pharma-ceutical scientists for many years. In 1995, Colin Gardner ofMerck introduced a flow chart showing synthesis of the APIand development of clinical supplies for first in human trialsin 1 year. In this early flow chart, drug substance synthesisand process development were carried out in parallel withpreformulation/formulation design/development and safetystudies. Despite the early introduction of the concept that anIND (investigational new drugs) can be submitted in 1 year,it has been difficult to achieve this goal except in very favor-able cases. One of the difficulties is the availability of API,and another one of the difficulties is accelerating toxicologystudies.
In 2007, Aptuit/SSCI introduced their IND-I-GO(INDIGO) program offering fast development in a ContractResearch Organization (CRO) environment. INDIGO wastailored to working with BCSClass II compounds and poorlysoluble compounds. This INDIGO offering was supportedby an example case study on the poorly soluble drug itra-conazole and was summarized in a recent publication [15].Additionally, Byrn et al. and Byrn and Henck outlined strate-gies based on solid-state chemistry for reducing developmenttime [16,17]. These publications contained muchmore detailon how to carry out screens and are discussed in more detailbelow. In this same timeframe, Chorus a Lilly-based firmfocused on fast development introduced their strategy for
10 SOLID-STATE PROPERTIES AND PHARMACEUTICAL DEVELOPMENT
accelerated development to Phase II [18]. In this early pub-lication, they suggested that it was possible to develop acompound to Phase II in 30 months for $3 million dollars incontrast to the industry average of 42months and $30milliondollars. The Chorus approach involves a virtual company thatheavily uses preferred CROs. Chorus has been quite success-ful, and Lilly has now established Chorus as an independententity.
In this same timeframe, PricewaterhouseCoopers intro-duced a concept of limited launchwithwhat they have termeda “live license” that permits a company tomarket a drug undervery restricted conditions. In one manifestation of this con-cept, they suggested launch of a drug after 1.5 years. Thedetails of this strategy are not clear, but it appears that theproposal involves introducing the drug for a limited popu-lation and then expanding use as clinical data allows. This,of course, would require the FDA to license drugs differ-ently. The main point of this strategy for our context is thatintroduction of a medicine after 1.5 years would require veryrapid development and very rapid FDA review. Regardlessof the details, it is clear that the solid form, the formulation,the synthesis of the drug and all of the other critical stepsoutlined in Table 1.1 would have to be accomplished quiterapidly.
Regardless of the model it is clear that in the future, devel-opment must be accelerated. Accelerated development isespecially dependent on the first year of activities. During
the first year three critical steps must be accomplished. Thedrug must be synthesized. The toxicology must be deter-mined to figure out the initial dose for first in human trials,and the solid form and formulation must be developed so thata medicine is available for first in human trials. This requiresthree groups to work together: API synthesis, toxicology,and pharmaceutical sciences. Figure 1.12 shows a detailed52-week strategy.
The top three bars show the synthesis of the API. Depend-ing on dose, several kilograms of API will be required fortoxicology studies that are shown in the fourth bar. A keyaspect of the toxicology study is the determination of thetoxicology formulation. As pointed out by the Merck group,the toxicology formulation can be critical for poorly solubledrugs. If not enough of the drug can be dissolved then it isimpossible to advance that lead [19]. The bottom four barsoutline the formulation and manufacture of clinical suppliesand the regulatory activities needed to file an IND. Engersand coworkers were able to meet the timelines in Figure 1.12and develop a mock IND for itraconazole [15].
Evenmore acceleration of the development timeframe canbe achieved if during the first year adaptive clinical trials aredesigned and biomarkers for the clinical trial endpoints aredefined and assays for these biomarkers developed. Adaptiveclinical trials allow merging of phase I and phase II studiesand can sometimes accelerate proof of concept studies [20].Adaptive clinical trials are often considered in two phases
FIGURE 1.12 Detailed 52-week strategy for accelerated drug development.
SOLID-STATE CHEMISTRY IN PREFORMULATION AND FORMULATION 11
exploratory and confirmatory and use biomarkers. Biomark-ers are quantifiable substances that can be correlated to a clin-ical response, for example, glucose for diabetes. Biomarkerscan include genes, gene products, enzymes, cytokines, oreven cells. Finding a biomarker can advance early decisionmaking and accelerate clinical trials.
One of the goals of accelerated development is to elim-inate compounds that are clinically unacceptable or cannotbe developed early so that more resources are available tofocus on compounds that are truly acceptable. For example,if a material is so insoluble its MAD (maximum absorbabledose) or MTD cannot be determined in animal studies thenthis must be determined as early as possible. Likewise if acompound has unacceptable neurotoxicity, this needs to bedetermined as early as possible. Thus, a strategy that focuseson the most soluble formulation early will provide impor-tant information in both of these cases. For this reason, someexperts are suggesting that initial formulations should useamorphous forms.
1.6 SOLID-STATE CHEMISTRY INPREFORMULATION AND FORMULATION
Figure 1.13 illustrates the important role that solid-state tech-nology plays in the entire development process includingresearch. In fact, a group from Merck (see above) in a Jour-nal of Medicinal Chemistry review has advocated movingsolid-state chemistry earlier and earlier in drug discovery inorder to ensure that a developable solid form is discovered
FIGURE 1.13 Role of solid-state technology in the pharmaceu-tical industry.
[19]. As mentioned above, the solid form is important intoxicology since an insoluble solid-state form will appear tobe nontoxic, perhaps falsely. The solid form is important indosage choice, the manufacturing process, purification, pro-cess development, and formulation. In some cases, productimprovements andmarketing can be facilitated by finding thebest solid form. For example, the Kaletra product (contain-ing lopinavir and ritonavir) is nowmarketed in an amorphousform that is stable and does not require refrigeration as didthe previous soft gel capsule. Solid forms are quite importantfor patents and regulatory filings as discussed above. Finally,the stability of the product can be critically related to thesolid form.
Particle size, like polymorphism, is one of themost criticalaspects of solid-state chemistry. The incorrect particle sizecan cause a change in the rate of dissolution and affect safety,efficacy, and performance. Figure 1.14 shows a classic study
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29.96 m suspensionμ
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FIGURE 1.14 Effect of particle size on blood levels. Source: Miller and Fincher, 1971 [21].Reproduced with the permission of Elsevier.
12 SOLID-STATE PROPERTIES AND PHARMACEUTICAL DEVELOPMENT
of the effect of particle size of a suspension on blood levelsof phenobarbital [21]. These data as well as the ICH Q6Adocument on specifications make it clear that particle size ofAPIs (drug substances) must be controlled especially if theyare poorly soluble.
Figure 1.12 illustrates one possibility for when solid-statechemistry is done during preformultion and formulationdesign. During this study, it is important to find a form withacceptable aqueous solubility. In many cases, this meansa form with fast kinetic solubility needs to be found. Ifpossible, the high solubility should be maintained until thedrug is absorbed from the GI tract. It may be necessary to usecrystallization inhibitors to prevent premature precipitationof the solid form. Additionally, the solid form must bechemically stable enough to not decompose during an INDtrial. An important goal is to find the form before the finalstep of the API synthesis. In this way the final form can beprepared in the last step. Additionally, if this can be achievedthe same form can be used for both toxicology and for firstin human studies.
After the first year additional solid-state and particlesize studies will be needed. First, it will be important toconfirm the results of the early solid-state studies. It isespecially important to do some additional screening toconfirm that the best solid form has been selected. Thereis time for additional salt screening studies and perhapseven cocrystal or nanocrystal screening studies. Furthermore,more complex formulations can be developed. For example,if possible a simple granulation process should be devel-oped. Alternatively, a roller compaction procedure can beinvestigated.
In many cases, when the dose of drug is dissolved it willbe in a supersaturated solution with respect to the most stablecrystal form. Thermodynamically, there will be a tendencyfor this most stable form to crystallize. This system has beentermed a supersaturating drug delivery system [22].
Screening is the approach to use to find the best solidform, amanufacturing process, and a crystallization inhibitor,if needed. Polymorph screening was suggested in the mid-1990s for regulatory purposes and to find the form thatresulted in the most desirable bioavailability. During theintervening years it has become clear that screening is crit-ical. In the early studies during the first year abbreviatedscreens should be used.
Solvents should include those used in the final crystalliza-tion steps and those used during formulation and process-ing such as water, methanol, ethanol, propanol, isopropanol,acetone, acetonitrile, ethyl acetate, hexane, and mixtures ifappropriate. New crystal forms can often be obtained bycooling hot saturated solutions or partly evaporating clearsaturated solutions. The solids produced are analyzed usingX-ray diffraction and at least one of the other methods. Inthese analyses, care must be taken to show that the methodof sample preparation (i.e., drying, grinding) has not affectedthe solid form.
Later, more complete screening studies are recommended.If a supersaturated solution is created it is important to screenfor a crystallization inhibitor [22]. As indicated, screening istypically done for polymorphs including amorphous forms,salts, cocrystals, and nanoparticulate formulations.
In addition to screening and selection of the best solidform and optimization/control of particle size, preformu-lation experiments are also carried out. These experimentsinclude determination of the partition coefficient (logP). Thisreflects the hydrophobicity of the drug and can be useful indetermining the BCS class. The solubility of all availableforms is determined as well as the degree of precipitation ofany solid forms. Since solubility can depend on solid form,the solubility is typically determined in aqueous buffers,organic solvents, surfactants and perhaps cyclodextrins andlipids. Solubility can be difficult to determine and should bedetermined under equilibrium conditions. The solution andsolid-state stability of the API is determined under stress con-ditions including extreme pH, temperature light, and humid-ity. This provides information on the intrinsic chemical stabil-ity of the system, and this knowledge is critical in formulationdevelopment. The pKa is also determined or calculated. Thisprovides important information on the acidity or basicity ofthe material.
Once the initial solid form has been selected based onthe above screening experiments, the stability of that form isdetermined under stress and accelerated conditions. This pro-vides important information on how to handle that particularform. The dissolution properties of this form are also mon-itored. This provides important information on what mighthappen in the GI tract.
Figure 1.15 illustrates the importance of studying the dis-solution rate of different forms [23]. In this study, the hydrateshowed normal dissolution behavior reaching a solubility ofabout 6 mg/mL. In contrast, the anhydrate showed rapidkinetic dissolution to form a supersaturated solution. Thissolution then crystallized after about 100 s to the hydrate.
FIGURE 1.15 Dissolution study of two different forms of theo-phylline. Source: Shefter and Higuchi, 1963 [23]. Reproduced withthe permission of Elsevier.
SOLID-STATE CHEMISTRY IN PREFORMULATION AND FORMULATION 13
30
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FIGURE 1.16 Enhancement of solubility and dissolution rateby salt formation. Source: Nelson, 1957 [24]. Reproduced with thepermission of Elsevier.
At the end of the experiment (500 s), equilibrium had beenreached and the solubilities of both forms were the same andequal to the hydrate form which was the solid form present.
Figure 1.16 shows a similar experiment by Nelson on saltsof theophylline [24]. In this experiment, the timeframe wasshort enough that theophylline hydrate did not crystallize.This figure shows the rapid dissolution rate achieved by somesalts. In fact, for some pharmaceutical salts, such as sodiumphenytoin, a solubility enhancement of about 1,000,000 isachieved. This clearly shows the desirability of finding saltforms and explains why a very large number of drugs aredeveloped as salts. Of course, salt forms are also known togreatly increase the bioavailability of solid forms.
A viable alternative to salt formation especially incases where a salt cannot be formed is to develop an
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FIGURE 1.17 Comparison of the bioavailability of a 2:1HPMC-P:itraconazole dispersion in dogs. Source: Enger et al., 2010 [15].Redrawn from data published.
amorphous form/formulation. There are several productscontaining amorphous forms on the market including Kaletraand Sporonox. A review reports that amorphous formulationscan result in as much as an 82× increase in bioavailability[25]. Law and coworkers reported greatly enhanced plasmaconcentrations of amorphous ritonavir over crystalline mate-rial. Ritonavir is one of the components in Kaletra [26].Figure 1.17 shows the results of studies of a 2:1 HPMC-P:itraconazole dispersion in dogs [15]. Clearly, the dispersionresults in a large increase in bioavailability.
Another alternative to salt formation is cocrystal for-mation. Figure 1.18 shows that a cocrystal enhanced thebioavailability of an amide containing API by about 4× [27].
FIGURE 1.18 Enhanced bioavailability of a cocrystal over the parent drug. Source: McNamaraet al., 2006 [27]. Reproduced with the permission of Springer.
14 SOLID-STATE PROPERTIES AND PHARMACEUTICAL DEVELOPMENT
In another interesting study of cocrystals, Childs andcoworkers at SSCI showed that cocrystals of fluoxetinehydrochloride could be formed that had faster and slowerdissolution rates than the parent [28]. This remains one ofthe only exampleswhere cocrystals resulted in both enhancedand reduced dissolution rates.
Amorphous and cocrystalline formulations are classifiedas supersaturated drug delivery systems as discussed above.Crystallization inhibitors are sometime used to prevent pre-mature crystallization for these formulations.
In addition to increasing solubility/dissolution rate, thesolid form can influence a number of other properties impor-tant for formulation including milling, blending, tablet-ing, dry filling, suspension formulation, and lyophilization.Transformations to other forms can also occur during theseprocesses.
1.7 LEARNING BEFORE DOING AND QUALITYBY DESIGN
It is possible to achieve accelerated development using qual-ity by design. Details are presented inChapter 24. Figure 1.19
shows the quality by design wheel used by both the FDAand Pfizer. This wheel illustrates the importance of productdesign and process design. In effect, we have been discussingproduct design in this chapter. By using the optimum solidform, it is possible to design a product with the desired sol-ubility. Once this has been achieved, the goal is to developa formulation that optimizes other properties (e.g., flow) sothat a viable product is available. Additionally, a process thatcan reproducibly make the formulation must be achieved.As outlined above often, with proper attention to the solidform a quality product can be designed rapidly. Thus, inmany respects, quality by design is based on preformulationstudies.
For early studies, a simple crystallization/amorphizationprocess followed by filling a solid form in a capsule is oftensufficient. This type of product can be manufactured fromsolid produced in a variety of ways including spray dryingor crystallization followed by capsule filling using one of thecommercially available automated capsule filling machines.
First, good analytical methods for physical characteriza-tion of the designed product must be developed. Then, criti-cal sources of variability in the designed product need to beaddressed: Is the solid form stable during its shelf life? What
Product Knowledge
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FIGURE 1.19 Quality by design strategies. Source: Byrn and Henck, 2007 [17]. Reproduced withthe permission of Elsevier.
